Genetically influenced childhood disruptive disorders, such as attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) have been consistently associated with the later development of substance-use disorders (SUDs). Yet relatively little is known about the mechanisms of genetic influence, or how genetic factors combine with specific environmental risks in the creation of these disorders, their maintenance, and their progression on to SUDs. Five years of renewal funding is sought so that we maywork to explicate these developmental processes. We have collected a large, community-based pre-adolescent sample, with equal representation of males and females, that has been enriched for the presence of ADHD, CD, and ODD. Composed of twins and their parents, our sample is genetically informative, providing for biometric modeling of the twin data as well as modeling of parent-offspring transmission effects, and we obtain DNA samples on all participants. We also assess a wide array of possible experiential risks, including parent-child relationships, parental monitoring, social support networks, neighborhood conditions, school-related experiences, and peer-group characteristics using self-report and in- person interview methods involving multiple informants (parents, children, teachers). Thus, in combination, we have the potential to address important hypotheses regarding the relationship between ADHD, CD, ODD and SUDs, including those that incorporate theories of gene-environment correlation and gene-environment interaction. Our initial funding allowed 500 pairs of 11-year-old twins and their parents to complete a day-long, in- person assessment. Their first follow-up assessment, at age 14, has begun. The additional requested five years of funding will allow for the completion of the age-14 assessment as well as the re-assessment of most of these individuals at age 17. The combination of this enriched sample with cases from our other ongoing research projects will yield more than 250 individuals with ADHD and 600 with CD by age 14. This high-risk sample will have comprehensive, longitudinal data and is well suited to investigate gender effects. During the next five years, we aim to understand gene-environment interplay that culminates in substance misuse and early-onset SUDs. Towards this goal we will work to: 1) characterize the inherited vulnerability for SUDs, including the role psychophysiological indicators and candidate genes play; 2) learn how early adolescent problem behaviors influence the course of SUD development; 3) delineate the role of intra and extra-familial socializing agents; 4) clarify the role of negative emotionality; and 5) address questions regarding the role of gender, including whether the inherited vulnerability varies by gender, and whether gender moderates the association between liability markers, environmental risk, and later substance-use problems.